WO2006115135A1 - Agent thérapeutique pour le syndrome du côlon irritable - Google Patents

Agent thérapeutique pour le syndrome du côlon irritable Download PDF

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Publication number
WO2006115135A1
WO2006115135A1 PCT/JP2006/308173 JP2006308173W WO2006115135A1 WO 2006115135 A1 WO2006115135 A1 WO 2006115135A1 JP 2006308173 W JP2006308173 W JP 2006308173W WO 2006115135 A1 WO2006115135 A1 WO 2006115135A1
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ibs
therapeutic agent
phenol
receptor antagonist
pyridine
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PCT/JP2006/308173
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English (en)
Japanese (ja)
Inventor
Mayumi Yamano
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Astellas Pharma Inc.
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Priority to JP2007514619A priority Critical patent/JPWO2006115135A1/ja
Priority to US11/911,668 priority patent/US8101580B2/en
Priority to EP06732080A priority patent/EP1872795A4/fr
Publication of WO2006115135A1 publication Critical patent/WO2006115135A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a therapeutic agent for irritable bowel syndrome.
  • IBS Irritable bowel syndrome
  • IBS is an abdominal pain, abdominal pain caused by abnormalities in the lower gastrointestinal tract, mainly the large intestine, despite the absence of organic diseases such as inflammation and tumors. Symptoms that cause chronic symptoms such as bloating, diarrhea, bowel movement abnormalities such as constipation, difficulty of bowel movement, and defecation tightness, and state of bowel movement. Is done. IBS is a relatively frequent disease that accounts for 20-50% of intestinal patients who visit outpatient clinics. The gender ratio is 1: 2 regardless of race, which is superior to women, and the prevalence rate is high among young people. .
  • IBS pharmacotherapy includes anticholinergic drugs for abdominal pain, tricyclic antidepressant drugs for improving gastrointestinal pain threshold reduction, antidiarrheal drugs for diarrhea for improving bowel movement abnormalities,
  • an anti-intestinal agent is used as a salt laxative for constipation.
  • Polycarbophil calcium is a drug that can be expected to be effective for both diarrhea and constipation. It forms a gel in the intestinal tract to adjust the hardness of the stool. And it has only a very limited effect.
  • Anti-anxiety drugs and antidepressants are used when anxiety and tension are extremely increased due to stress, but they are administered at lower doses than those used in the psychiatric field. Improvement may not be effective for bowel movement abnormalities.
  • Anti-anxiety drugs are generally IBS symptoms and may be effective for diarrhea and abdominal pain, but tend to be less effective for constipation [0004] Drugs that have attracted attention in recent years include arosetron, a 5-HT3 receptor antagonist, and tegaserod, a 5-HT4 receptor agonist, which are used for diarrhea and constipation, respectively. These drugs improve bowel movements by regulating intestinal motility, and their effects are rapid.
  • arosetron has a relatively high improvement rate of 40-60% for abdominal symptoms and diarrhea, constipation appears in 30-35% of patients, and ischemic colitis (a fatal case) (Including non-patent literature 1).
  • the effect of tegaserod on the constipation type is not sufficient, and there is concern about tachyphylaxis (a phenomenon in which resistance is produced by repeated administration of drugs within a short time).
  • Bombesin / GRP is a cerebral intestinal peptide and expresses various physiological actions through the bombesin receptor. Bombesin receptors are classified into three subtypes: BB1, BB2, and BB3 / B RS3 (bombesin receptor subtype-3). Neuromedin B and GRP are identified as mammalian endogenous ligands for BB1 and BB2 receptors, respectively. Has been. It has been reported that GRP and BB2 receptors significantly increase GRP in the amygdala and hypothalamus when stress is applied to a force animal that exists ubiquitously in the brain, gastrointestinal tract, etc. (Non-patent Document 3).
  • BB2 receptor antagonists administered intraventricularly have also been reported to suppress ACTH elevation in rats subjected to restraint stress (Non-patent Document 4) of peripheral GRP and BB2 receptors against force stress responses.
  • No report on engagement [0007] The role of the GRP / BB2 receptor in gastrointestinal tract function is as follows: vasoactive intestinal peptide (vasoactive intestinal peptide in guinea pigs) (VIP)) and coexisting with water have been reported (Non-patent Document 7).
  • VIP vasoactive intestinal peptide
  • a peptide compound (RC-3095) represented by the formula (I) is known as a BB2 receptor antagonist (Non-patent Document 8 and Patent Document 1).
  • BB2 receptor antagonists include, for example, a compound represented by the formula (II) (BIM26226, Non-Patent Document 12 and Patent Document 2), [Chemical 2]
  • Patent Documents 1 to 8 and the like have been reported. However, these references also report on the effectiveness and potential use of BB2 receptor antagonists for IBS! /.
  • (2E) -3- [5- (4-Trophele) -2-furyl] -1-phenol-2-propen-1-one (CA S Registry No.38898-76 -9; Non-patent document 15) has been reported as an intermediate for the synthesis of antibacterial compounds, but it has been reported for its effectiveness against BB2 receptor antagonism and IBS. ,.
  • Non-Patent Literature 1 "American Journa”
  • Non-Patent Document 2 "Gut” (UK), 1998, No. 42, p.845-849
  • Non-Patent Document 3 "The Journal of Neuroscience” (USA), 1998, Vol. 18, p.4758-4766
  • Non-Patent Document 4 "Life Sciences” (The Netherlands), 2002, No. 70, p. 2953-2966
  • Non-Patent Document 5 “Gastroenterology, (USA), 1991, No. 100, P.980-985
  • Non-Patent Document 6 “Neurogastroenterology and Motility” (UK), 1997, 9th, p.265-270
  • Non-Patent Document 7 “Arnials of the New York Academy of Science”, (USA), 2000, 921 .420-424
  • Non-Patent Document 8 “The Prostate” (USA), 1994, 25th pp. 29-38
  • Non-Patent Document 9 “Cancer” (USA) ), 1998, 83, p.1335-1343
  • Non-Patent Document 10 “British Journal of Cancer”, 2000, 83, p.906-913,
  • Non-Patent Document 11 “Cancer” (USA), 2000, No. 88, p.1384-1392
  • Non-Patent Document 12 “Regulatory Peptides”, (Netherlands), 1994 Year 53, P.165-173
  • Non-Patent Document 13 “Bioorganic & Medicinal Chemistry Letters”, (Netherlands), 1992, II, ⁇ .333-338
  • Non-Patent Document 14 “Bio Organic and Medicinal Chemistry Letters], (Netherlands), 1998, 8th, ⁇ .2589-2594
  • Non-Patent Document 15 “Il'Farmaco” (Netherlands), 2001, 56th, 10th, p.919-927
  • Patent Literature 1 Pamphlet of International Publication No. 92Z09626
  • Patent Document 2 International Publication No. 91Z9102746 Pamphlet
  • Patent Document 3 International Publication No. 92Z07830 Pamphlet
  • Patent Document 4 Pamphlet of International Publication No.98Z07718
  • Patent Document 5 Japanese Patent Laid-Open No. 7-258081
  • Patent Document 6 International Publication No.OOZ09115 Pamphlet
  • Patent Document 7 International Publication No. 02Z40469 Pamphlet
  • Patent Document 8 International Publication No.02Z40475 Pamphlet
  • the existing IBS therapeutic agent does not show sufficient efficacy for both abdominal symptoms and abnormal bowel movement, and is not sufficiently satisfactory in terms of safety. There is an urgent need to provide an IBS therapeutic agent with excellent efficacy and safety.
  • the present inventors have conducted intensive research for the purpose of providing an IBS therapeutic agent exhibiting excellent efficacy against both abdominal symptoms and abnormal bowel movements.
  • BB2 receptor antagonist force stress stool excretion models such as RC-3095 are effective for bowel movement abnormalities.
  • RC-3095 was found to be effective for abdominal symptoms in an abdominal pain model with colonic dilation stimulation using abdominal muscle contraction response as an index.
  • the present invention was completed based on the knowledge that it is an IBS therapeutic agent exhibiting high efficacy.
  • a therapeutic agent for irritable bowel syndrome comprising a bombesin type 2 (BB2) receptor antagonist as an active ingredient.
  • a BB2 receptor antagonist is a compound represented by the formula (I),
  • the therapeutic agent according to any one of (1) to sol (4) which is a compound selected from the group that also has strength, or a pharmaceutically acceptable salt thereof.
  • BB2 receptor antagonist is a compound represented by the formula (I) according to (5),
  • a method for treating IBS comprising administering an effective amount of a BB2 receptor antagonist to a patient.
  • the BB2 receptor antagonist is a compound represented by the formula (I) according to (5),
  • the therapeutic agent for IBS of the present invention exhibits an excellent therapeutic effect of IBS by antagonizing the BB2 receptor.
  • the existing IBS therapeutic agent does not show sufficient efficacy for both abdominal symptoms and bowel movements, whereas the IBS therapeutic agent of the present invention shows effectiveness for both abdominal symptoms and abnormal bowel movements. It is useful as a highly effective treatment for IBS.
  • FIG. 1 shows the results of plasma GRP concentration in Example 2.
  • FIG. 2 shows the results of the RC-3095 administration group in Example 3.
  • FIG. 3 shows the results of the administration group of 2- [4- (1-naphthyl) -5-phenyl-1,3-thiazol-2-yl] pyridine (Compound 1) in Example 3.
  • FIG. 5 2-chloro-5-nitro-N- (4- ⁇ [2- (pyridin-3-yl) piperidine-1-yl] sulfurol ⁇ in Example 3 (B) The results of the benzamide (compound 3) administration group are shown.
  • FIG. 7 shows N- [3- (l, 3-benzothiazol-2-yl) -6-isopropyl-4,5,6, in Example 3.
  • FIG. 8 shows the results of the RC-3095 administration group in Example 4.
  • FIG. 9 shows the results of the RC-3095 administration group in Example 5.
  • IBS irritable bowel syndrome
  • diarrhea type IBS includes diarrhea type IBS, constipation type IBS, and alternating type IBS.
  • the indication of the therapeutic agent of the present invention is preferably diarrhea type IBS or alternating type IBS, and particularly preferably diarrhea type IBS.
  • “Abnormal bowel movement” means constipation and Z or diarrhea. “Abdominal symptoms” means abdominal pain, abdominal fullness and Z or abdominal discomfort.
  • a “BB2 receptor antagonist” is a compound that acts antagonistically with the agonist GRP and inhibits the action via the BB2 receptor.
  • a BB2 receptor antagonist is not particularly limited as long as it has a therapeutic effect on symptoms such as abnormal IBS stool and Z or abdominal symptoms.
  • the compound has a therapeutic effect on both abnormal bowel movements and abdominal symptoms.
  • BB2 receptor antagonists can be purchased, or can be easily obtained by known production methods, methods described in the production examples described later, or methods obvious to those skilled in the art.
  • the present invention includes a therapeutic agent using one or more of these BB2 receptor antagonists in combination.
  • the BB2 receptor antagonist may form an acid addition salt or a salt with a base, and is included in the present invention as long as the salt is a pharmaceutically acceptable salt.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid
  • Acid addition salts with organic acids such as lactic acid, phosphoric acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, sodium, potassium, magnesium, calcium, aluminum, etc.
  • Inorganic bases salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine and orthine, and ammonium salts.
  • the BB2 receptor antagonist or a pharmaceutically acceptable salt thereof may be various hydrates or solvates, and further includes those polymorphic substances.
  • the pharmaceutically acceptable salts of these BB2 receptor antagonists can be easily produced by salt formation methods that can be usually employed by those skilled in the art.
  • the BB2 receptor antagonist includes geometric isomers, tautomers, optical isomers, and the like. Various mixtures of stereoisomers and isolated ones are included. These isomers can be isolated and purified by a known method such as extraction, precipitation, fractional chromatography, fractional crystallization, recrystallization and the like. The optical isomers can be resolved by a conventional method such as fractional crystallization by recrystallization with an appropriate salt or column chromatography.
  • the BB2 receptor antagonist includes a pharmacologically acceptable prodrug.
  • a pharmacologically acceptable prodrug is a compound that is converted to a BB2 receptor antagonist by solvolysis or under physiological conditions.
  • Prodrug-forming groups include “Progress in Medicine” 1985, May 5, p.2157-2161 and “Development of pharmaceuticals”, Yodogawa Shoten, 1990, No. 7, Examples include groups described in Molecular Design, p.163-198. Prodrugs of these BB2 receptor antagonists can be easily produced by methods that can be generally employed by those skilled in the art.
  • a preparation containing a BB2 receptor antagonist as an active ingredient is prepared using a carrier, excipient, and other additives that are usually used for formulation.
  • Administration is oral by tablet, pill, capsule, granule, powder, liquid, etc., or parenteral by intravenous, intramuscular injection, suppository, transdermal agent, nasal agent, inhalant, etc. Either form may be used.
  • the dose is determined appropriately according to the individual case, taking into account the symptoms, age of the subject, sex, etc.In general, in the case of oral administration, it is about 0.001 mg / kg to 100 mg / kg per day for an adult. This is administered once or divided into 2 to 4 times. When administered intravenously depending on the symptoms, it is usually administered once or multiple times in a range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of inhalation, it is usually administered once or multiple times in a range of 0.0001 mg / kg to 1 mg / kg per adult.
  • Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention.
  • one or more active substance powers and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, Mixed with polybulurpyrrolidone, magnesium aluminate metasilicate, etc.
  • the composition may contain an inert additive, for example, a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a solubilizer, and a solubilizer according to a conventional method.
  • Tablets or pills may be sugar-coated or Can be coated with a gastric or enteric coating.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and are generally used inert solvents such as purified water. , Including ethanol.
  • the composition may contain solubilizers, wetting agents, suspending agents and other auxiliary agents, sweeteners, corrigents, fragrances and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous solvent include distilled water for injection and physiological saline.
  • non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80 (trade name), and the like.
  • Such a composition may further contain isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, solubilizers, and solubilizers. These are sterilized, for example, by filtration through a bacteria-retaining filter, blending with a bactericide, or irradiation. In addition, these can be used by producing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
  • Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods.
  • an excipient and as Ratatosu Ya starch furthermore, P H adjusting agent, a preservative, a surfactant, a lubricant, a stabilizing agent, a thickening agent, or the like may be added as appropriate.
  • P H adjusting agent a preservative
  • a surfactant e.g., a lubricant, a stabilizing agent, a thickening agent, or the like
  • a thickening agent e.g., a thickening agent, or the like
  • an appropriate device for inhalation or insufflation can be used.
  • the compound alone or as a powder in a formulated mixture, or in combination with a pharmaceutically acceptable carrier or suspension can be administered as
  • dry powder inhalers dry powder or powder-containing capsules that can be used for single or multiple administrations can be used.
  • a suitable propellant for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.
  • Example 1 BB2 receptor antagonist activity
  • BB2 receptor binding experiments were performed using membrane preparations prepared from PC-3 cells derived from human prostate cancer. After culturing PC-3 cells in RPMI-1640 medium containing 5% ushi fetal serum, a membrane preparation was prepared by the following method. 50 mM Tris-HCl buffer (pH 7.4, containing 0.2 mg / ml trypsin inhibitor and 0.2 mg / ml benzamidin) was added to the cells peeled off by trypsin treatment, and homogenized with polytron. The cell suspension was centrifuged at 1,500 rpm for 10 minutes, and the resulting supernatant was ultracentrifuged at 37,000 rpm for 1 hour. The precipitate was suspended in the above buffer to a concentration of 0.4 mg protein / ml and stored at -80 ° C.
  • Tris-HCl buffer pH 7.4, containing 0.2 mg / ml trypsin inhibitor and 0.2 mg / ml benzamidin
  • a BB2 receptor binding experiment was performed by the following method, and the receptor antagonistic activity of the test compound was calculated.
  • Membrane preparation 50 ⁇ l in 96-well assembly plate, assembly buffer (20 mM HEPES-H BSS, 0.1% urine serum albumin and 0.1 mg / ⁇ bacitracin, pH 7.4) 50 ⁇ 1, 1 25 I [ Tyr 4 ] Bombesin (0.075 nM) and 2 ⁇ l of the test compound dissolved in dimethyl sulfoxide were added and incubated at room temperature for 2 hours. Nonspecific binding was measured using 1 ⁇ bombesin. After the incubation was completed, the reaction solution was filtered on a Whatman GF / B filter after soaking in 0.5% polyethyleneimine.
  • the radioactivity on the filter was measured using a microplate scintillation counter (Topcount, Perkin Elma).
  • Topcount Perkin Elma
  • the 50% binding inhibitory concentrations of RC-3095, Compound 1, Compound 2, Compound 3, Compound 4, and Compound 5 were 20, 504, 1330, 342, 398, and 383 nM, respectively.
  • Example 3 Restraint stress fecal discharge model
  • RC-3095 is in physiological saline
  • Compound 1 Compound 3 and Compound 5 are in physiological saline containing 5% ethanol + 5% Cremophor
  • Compound 2 and Compound 4 are in 20% propylene glycol + 20% Tween 80 Used by dissolving in water for injection.
  • a restraint stress cage (trade name: KN-469, Natsume Seisakusho). The number of feces excreted within 1 hour after the start of restraint was measured. The normal group was placed in an individual cage, and the number of feces excreted in 1 hour was measured in the same manner.
  • RC-3095 showed a dose-dependent suppressive effect on fecal excretion, and the 50% inhibitory dose was 5.2 mg / kg.
  • Compound 1 was shown to produce about 83% of fecal discharge suppression at 10 mg / kg ( Figure 3).
  • the 50% inhibitory doses for restrained stress stool excretion of Compound 2, Compound 3, Compound 4, and Compound 5 were 34.3, 19.0, 13.5, and 15.6 mg / kg, respectively ( Figures 4-7). From this, it was confirmed that the BB2 receptor antagonist showed the effect of diarrhea-type IBS in improving the bowel symptoms.
  • Example 4 Conditioned-fear stress (CFS) stool discharge model
  • Non-fasted male sprag-Dawley rats were used.
  • a rat is placed in an electric shock device (17 x 17 x 39 cm, product name: CB2000, O'Hara Co., Ltd.) with an electrode grid fitted on the floor.
  • a current of 2.5-mA was applied 5 times per minute for a total of 15 times, and conditioned by light irradiation with three 40 W bulbs during electric shock.
  • the normal group was put into the measuring device according to the same protocol, the electric shock was strong.
  • the rats were placed in the electric shock device again, and subjected to CFS loading in which 3 seconds of warning sound and 5 seconds of light irradiation were applied for 30 minutes.
  • CFS loading 3 seconds of warning sound and 5 seconds of light irradiation were applied for 30 minutes.
  • the wet weight of feces excreted 30 minutes after the start of CFS loading was measured.
  • the measured force was also excluded from defecation immediately after placing the rat in the measuring device.
  • RC-3095 showed a dose-dependent inhibitory effect on fecal excretion, and showed a significant inhibitory effect at 10 mg / kg. From this, it was confirmed that the BB2 receptor antagonist showed the effect of improving bowel movement symptoms of diarrhea type IBS.
  • Example 5 Abdominal pain model by large intestine expansion stimulation using abdominal muscle contraction reaction as an index Non-fasting male Wistar rats were used. Under anesthesia with pentobarbital, an electromyographic electrode (trade name: M-1.5I, Star Medical Co., Ltd.) was sewn to the external oblique muscle. The electrode cord was subcutaneously exposed to the force near the occipital region, and was protected with a protective jacket made by processing the Berg mouth. The experiment was conducted more than 5 days after the operation.
  • a latex cell with a length of 5-6 cm was inserted from the rat anus under light ether anesthesia and adjusted so that the end of the cell was 2 cm from the anus.
  • the catheter continued with balloon force.
  • the catheter was fixed to the ridge with tape, and connected to a pressure transducer and a plastic bottle filled with water via a three-way stopcock.
  • the plastic bottle was allowed to rise at a constant rate using a motorized device, and the rat's colonic rectum was expanded by raising the height of the plastic bottle.
  • the lane internal pressure signal was amplified by a strain pressure amplifier. After recovery from ether anesthesia in a cage (23.5 x 19 x 19 cm), a colonic rectal dilatation was performed.
  • EMG activity is amplified by bioelectric amplifier (trade name: AB-621G, Nihon Kohden) and data recording interface (trade name: 1401plus, Cambridge 'Elect Mouth-Cock' Design (Cambridge Electronic Design); Cambridge (Cambridge, UK). Colon-rectal dilatation was repeated at 4-minute intervals until the end of the experiment. The compound was administered 2 minutes after taking the pre-dose value and repeated colon-rectal dilatation up to 60 minutes after administration. The threshold before the compound administration was set to 100%, and the area under the curve (AUC) of the threshold until 60 minutes after administration was calculated.
  • AUC area under the curve
  • RC-3095 showed an abdominal pain threshold increasing action in a dose-dependent manner, and 3 and 10 mg / kg administration showed a significant increasing action. From this, it was confirmed that the BB2 receptor antagonist has an abdominal pain improving action.
  • Compound 1 is a novel substance.
  • the raw material compounds used in the production examples include new substances. A method for producing such a compound is described as a reference production example.
  • N- (3,4-dimethoxyphenol) benzenesulfonamide 1.99 g of ⁇ , ⁇ -dimethylformamide solution (30 mL) was charged with 296 mg of sodium hydride under ice-cooling and stirred at room temperature for 30 minutes. Thereafter, 0.75 mL of bromoethyl acetate was added and stirred for 2 hours.
  • the reaction mixture was poured into ice water, acidified with 1M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the resulting residue was purified by silica gel column chromatography using ethyl acetate: n-hexane (1: 2) as an elution solvent, ] 2.47 g of acetate was obtained as a pale yellow oil.
  • Table 1 below shows the structural formulas of Compounds 1 to 5.
  • Me means methyl.
  • HC1 is described in the structural formula, it indicates that the compound is a hydrochloride.
  • the BB2 receptor antagonist represented by RC-3095 is an IBS therapeutic agent showing excellent efficacy for both abdominal symptoms and bowel movement abnormalities. Therefore, according to the present invention, it has become possible to provide an IBS therapeutic agent comprising a bombesin 2 (BB2) receptor antagonist as an active ingredient, which exhibits excellent efficacy against both abdominal symptoms and bowel movement abnormalities. .
  • BB2 bombesin 2

Abstract

L'invention a pour objet un agent thérapeutique pour le syndrome du côlon irritable (SCI) excellent en termes d'efficacité et de sécurité. Il a été montré qu'un antagoniste des récepteurs de la bombésine 2 (BB2), tel que représenté par RC-3095, était un agent thérapeutique pour le syndrome du côlon irritable (SCI) exerçant une excellente efficacité à la fois sur les symptômes abdominaux et sur les troubles de la défécation. Par conséquent, selon l'invention, il devient possible de disposer d'un agent thérapeutique pour le syndrome du côlon irritable (SCI) contenant comme ingrédient actif un antagoniste des récepteurs de la bombésine 2 (BB2) exerçant une excellente efficacité à la fois sur les symptômes abdominaux et sur les troubles de la défécation.
PCT/JP2006/308173 2005-04-21 2006-04-19 Agent thérapeutique pour le syndrome du côlon irritable WO2006115135A1 (fr)

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WO2008061247A2 (fr) * 2006-11-16 2008-05-22 The Regent Of The University Of California Inhibiteurs à composé sulfonanilide benzène de transporteurs d'urée
WO2008146774A1 (fr) 2007-05-28 2008-12-04 Astellas Pharma Inc. Dérivé de tétrahydroisoquinolin-1-one ou sel de celui-ci
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US8101580B2 (en) 2005-04-21 2012-01-24 Astellas Pharma Inc. Therapeutic agent for irritable bowel syndrome
WO2007091948A3 (fr) * 2006-02-07 2007-10-04 Astrazeneca Ab Nouveaux composés
WO2008061247A2 (fr) * 2006-11-16 2008-05-22 The Regent Of The University Of California Inhibiteurs à composé sulfonanilide benzène de transporteurs d'urée
WO2008061247A3 (fr) * 2006-11-16 2008-07-10 Alan S Verkman Inhibiteurs à composé sulfonanilide benzène de transporteurs d'urée
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EP2149561A1 (fr) * 2007-05-28 2010-02-03 Astellas Pharma Inc. Dérivé de tétrahydroisoquinolin-1-one ou sel de celui-ci
EP2149561A4 (fr) * 2007-05-28 2011-09-07 Astellas Pharma Inc Dérivé de tétrahydroisoquinolin-1-one ou sel de celui-ci
US9150541B2 (en) 2007-05-28 2015-10-06 Seldar Pharma Inc. Tetrahydroisoquinolin-1-one derivative or salt thereof
AU2008255815B2 (en) * 2007-05-28 2012-02-02 Seldar Pharma Inc Tetrahydroisoquinolin-1-one derivative or salt thereof
US8486970B2 (en) 2007-05-28 2013-07-16 Seldar Pharma Inc. Tetrahydroisoquinolin-1-one derivative or salt thereof
US9526719B2 (en) 2007-05-28 2016-12-27 Seldar Pharma Inc. Tetrahydroisoquinolin-1-one derivative or salt thereof
JP5336359B2 (ja) * 2007-05-28 2013-11-06 セルダー ファーマ インコーポレイテッド テトラヒドロイソキノリン−１−オン誘導体またはその塩
WO2009077956A2 (fr) * 2007-12-14 2009-06-25 Alla Chem, Llc INHIBITEURS HÉTÉROCYCLIQUES D'UNE CASCADE DE SIGNAUX Hh, COMPOSITIONS MÉDICINALES À BASE DE CES INHIBITEURS ET MÉTHODES DE TRAITEMENT DE MALADIES PROVOQUÉES PAR L'ACTIVITÉ ABERRANTE DU SYSTÈME DE SIGNALISATION Hh
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WO2009077956A3 (fr) * 2007-12-14 2009-10-22 Алла Хем, Ллс INHIBITEURS HÉTÉROCYCLIQUES D'UNE CASCADE DE SIGNAUX Hh, COMPOSITIONS MÉDICINALES À BASE DE CES INHIBITEURS ET MÉTHODES DE TRAITEMENT DE MALADIES PROVOQUÉES PAR L'ACTIVITÉ ABERRANTE DU SYSTÈME DE SIGNALISATION Hh
WO2009123080A1 (fr) * 2008-04-01 2009-10-08 アステラス製薬株式会社 Composé d'indolinone

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